This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The HIV pandemic continues with an estimated 13,000 new infections each day, the vast majority acquired through heterosexual sex. Currently, no vaccine is available to prevent HIV and it is unlikely that one will be developed soon. This highlights the critical need for an effective, female-controlled HIV prevention strategy such as a vaginally-applied microbicide gel, which can enable women to protect themselves from transmission. Because first generation microbicides have been proved ineffective, highlighted by the disappointing results from the MDP 301 Phase III trial of PRO 2000 vaginal microbicide gel, gels formulated with antiretroviral drugs has gained considerable attention as a potential biomedical intervention to protect high-risk HIV-negative people from becoming infected. These strategies are more promising because they can deliver a high dose of potent drugs that can block HIV replication at the mucosal point of entry. To this end, we have successfully formulated and evaluated several gels containing single or combinations of nucleoside/nucleotide reverse transcriptase (emtricitabine and tenofovir) or integrase (Raltegravir) inhibitors. Our efficacy studies show that gels containing tenofovir (TFV) alone or in combination with emtricitabine (FTC) can fully protect against vaginal transmission using a low-dose, repeat SHIV challenge model in pigtailed macaques. In addition, follow-up studies evaluating the window of protection showed that TFV provided long-lasting protection and remained in vaginal tissues for days following a single gel application, suggesting that non-coital daily gel use may not be necessary to achieve protection. We also completed studies to assess the efficacy of gels with integrase inhibitors and show them to be highly protective for both pre- and post exposure prophylaxis, demonstrating for the first time the utility of this class of drugs. These animal studies advance the field by highlighting the high efficacy of topical antiretroviral prophylaxis and aid in future clinical trial designs.